We have been studying the rabbit appendix and find that it is an important site of development of the cells destined to produce protective antibodies. In the young rabbit, there is rapid growth and expansion of B lymphocytes in the appendix, and positive and negative selection events appear to occur within this organ. Because of the remarkable finding that the developing rabbit appendix is a site of repertoire diversification and selection, we are extending our findings from the rabbit model to studies of the developing human immune system. We are initiating investigations aimed at determining whether the human appendix or other Gut Associated Lymphoid Tissues (GALT) are important sites of early events in human B cell development, diversification and selection. In addition we are asking whether appendix functions in the diversification of the antibody repertoire during repopulation of other lymphoid organs, if the repertoire diversity or B-lymphocyte numbers of these organs are reduced by a genetic defect, irradiation or chemotherapy. Studies of human embryonic development show that the distal midgut and ileocecal portion of the digestive system, including the appendix, are developmentally homologous with the bursa of Fabricius. In view of our new findings in the rabbit model that indicate that the rabbit appendix has functions similar to the avian bursa, we believe it is important to conduct a new evaluation of the role of human GALT in development of the human immune repertoire and mucosal immunity.